Angiotensin-converting enzyme insertion/deletion polymorphism and severe hypoglycemia complicating type 2 diabetes: the Fremantle Diabetes Study.

Aims/hypotheses: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) gene I/D polymorphisms independently predict severe hypoglycemia in community-dwelling type 2 patients.

Methods: Six hundred and two patients who were ACE genotyped at baseline and assessed in 1998 were followed up to the end of June 2006. Severe hypoglycemia was defined as that requiring documented health service use as the primary diagnosis. Cox proportional hazards modeling was used to determine the predictors of first episode and zero-inflated negative binomial regression modeling identified predictors of frequency.

Results: Forty-nine patients (8.1%) experienced 63 episodes of severe hypoglycemia. After adjusting for previously identified significant independent predictors of time to first episode, both ACE DD genotype and ACE inhibitor therapy, but not their interaction, added to the model [hazard ratio (95% confidence interval): 2.34 (1.29-4.26), P = 0.006, and 1.77 (0.99-3.13), P = 0.052, respectively]. Similarly, after adjusting for previously identified risk factors for multiple episodes of severe hypoglycemia, ACE DD genotype was independently associated with increased risk [incidence relative risk (95% confidence interval): 1.80 (1.00-3.24), P = 0.050].

Conclusions/interpretation: ACE DD genotype was associated with an approximately 2-fold increased risk of the first episode of severe hypoglycemia and its subsequent frequency in well-characterized patients with type 2 diabetes. Consistent with previous case-control studies, ACE inhibitor therapy was a weak predictor of severe hypoglycemia. ACE I/D genotyping might provide useful adjunctive prognostic information when intensive glycemic control measures are contemplated.